Alzheimer's disease - Wikipedia

Alzheimer's disease (AD) is a neurodegenerative disease that usually starts slowly and progressively worsens. ... It is the cause of 60–70% of cases of dementia. Alzheimer'sdisease FromWikipedia,thefreeencyclopedia Jumptonavigation Jumptosearch Progressiveandterminalneurodegenerativediseasecharacterisedbymemoryloss "Alzheimer"redirectshere.Forotheruses,seeAlzheimer(disambiguation). Thisarticleneedstobeupdated.Pleasehelpupdatethisarticletoreflectrecenteventsornewlyavailableinformation.(March2021) MedicalconditionAlzheimer'sdiseaseDrawingcomparinganormalagedbrain(left)andthebrainofapersonwithAlzheimer's.Characteristicsthatseparatethetwoarepointedout.PronunciationˈaltshʌɪməzSpecialtyNeurologySymptomsMemoryloss,problemswithlanguage,disorientation,moodswings[1][2]ComplicationsDehydrationandpneumoniaintheterminalstage[3]UsualonsetOver65yearsold[4]DurationLongterm[2]CausesPoorlyunderstood[1]RiskfactorsGenetics,headinjuries,depression,hypertension[1]DiagnosticmethodBasedonsymptomsandcognitivetestingafterrulingoutotherpossiblecauses[5]DifferentialdiagnosisNormalaging,[1]Lewybodydementia,[6]Trisomy21.[7]MedicationAcetylcholinesteraseinhibitors,NMDAreceptorantagonists(smallbenefit)[8]PrognosisLifeexpectancy3–9years[9]Frequency50million(2020)[10] Alzheimer'sdisease(AD)isaneurodegenerativediseasethatusuallystartsslowlyandprogressivelyworsens.[2]Itisthecauseof60–70%ofcasesofdementia.[2][11]Themostcommonearlysymptomisdifficultyinrememberingrecentevents.[1]Asthediseaseadvances,symptomscanincludeproblemswithlanguage,disorientation(includingeasilygettinglost),moodswings,lossofmotivation,self-neglect,andbehavioralissues.[2]Asaperson'sconditiondeclines,theyoftenwithdrawfromfamilyandsociety.[12]Gradually,bodilyfunctionsarelost,ultimatelyleadingtodeath.[13]Althoughthespeedofprogressioncanvary,thetypicallifeexpectancyfollowingdiagnosisisthreetonineyears.[9][14] ThecauseofAlzheimer'sdiseaseispoorlyunderstood.[12]Therearemanyenvironmentalandgeneticriskfactorsassociatedwithitsdevelopment.ThestrongestgeneticriskfactorisfromanalleleofAPOE.[15][16]Otherriskfactorsincludeahistoryofheadinjury,clinicaldepression,andhighbloodpressure.[1]Thediseaseprocessislargelyassociatedwithamyloidplaques,neurofibrillarytangles,andlossofneuronalconnectionsinthebrain.[13]Aprobablediagnosisisbasedonthehistoryoftheillnessandcognitivetestingwithmedicalimagingandbloodteststoruleoutotherpossiblecauses.[5]Initialsymptomsareoftenmistakenfornormalaging.[12]Examinationofbraintissueisneededforadefinitediagnosis,butthiscanonlytakeplaceafterdeath.[13]Goodnutrition,physicalactivity,andengagingsociallyareknowntobeofbenefitgenerallyinaging,andthesemayhelpinreducingtheriskofcognitivedeclineandAlzheimer's;in2019clinicaltrialswereunderwaytolookatthesepossibilities.[13]Therearenomedicationsorsupplementsthathavebeenshowntodecreaserisk.[17] Notreatmentsstoporreverseitsprogression,thoughsomemaytemporarilyimprovesymptoms.[2]Affectedpeopleincreasinglyrelyonothersforassistance,oftenplacingaburdenonthecaregiver.[18]Thepressurescanincludesocial,psychological,physical,andeconomicelements.[18]Exerciseprogramsmaybebeneficialwithrespecttoactivitiesofdailylivingandcanpotentiallyimproveoutcomes.[19]Behavioralproblemsorpsychosisduetodementiaareoftentreatedwithantipsychotics,butthisisnotusuallyrecommended,asthereislittlebenefitandanincreasedriskofearlydeath.[20][21] Asof2020,therewereapproximately50millionpeopleworldwidewithAlzheimer'sdisease.[10]Itmostoftenbeginsinpeopleover65 yearsofage,althoughupto10%ofcasesareearly-onsetaffectingthoseintheir30stomid-60s.[13][4]Itaffectsabout6%ofpeople65yearsandolder,[12]andwomenmoreoftenthanmen.[22]ThediseaseisnamedafterGermanpsychiatristandpathologistAloisAlzheimer,whofirstdescribeditin1906.[23]Alzheimer'sfinancialburdenonsocietyislarge,withanestimatedglobalannualcostofUS$1 trillion.[10]Alzheimer'sdiseaseiscurrentlyrankedastheseventhleadingcauseofdeathintheUnitedStates.[24] Contents 1Signsandsymptoms 1.1Firstsymptoms 1.2Earlystage 1.3Middlestage 1.4Latestage 2Causes 2.1Genetic 2.2Otherhypotheses 3Pathophysiology 3.1Neuropathology 3.2Biochemistry 3.3Diseasemechanism 4Diagnosis 4.1Criteria 4.2Techniques 5Prevention 5.1Medication 5.2Lifestyle 6Management 6.1Pharmaceutical 6.2Psychosocial 6.3Caregiving 6.4Diet 7Prognosis 8Epidemiology 9History 10Societyandculture 10.1Socialcosts 10.2Caregivingburden 10.3Media 11Researchdirections 11.1Treatmentandprevention 11.2Causeanddiagnosis 12References 13Furtherreading 14Externallinks Signsandsymptoms ThecourseofAlzheimer'sisgenerallydescribedinthreestages,withaprogressivepatternofcognitiveandfunctionalimpairment.[25][13]Thethreestagesaredescribedasearlyormild,middleormoderate,andlateorsevere.[25][13]Thediseaseisknowntotargetthehippocampuswhichisassociatedwithmemory,andthisisresponsibleforthefirstsymptomsofmemoryimpairment.Asthediseaseprogressessodoesthedegreeofmemoryimpairment.[13] Firstsymptoms StagesofatrophyinAlzheimer's. Thefirstsymptomsareoftenmistakenlyattributedtoagingorstress.[26]DetailedneuropsychologicaltestingcanrevealmildcognitivedifficultiesuptoeightyearsbeforeapersonfulfillstheclinicalcriteriafordiagnosisofAlzheimer'sdisease.[27]Theseearlysymptomscanaffectthemostcomplexactivitiesofdailyliving.[28]Themostnoticeabledeficitisshorttermmemoryloss,whichshowsupasdifficultyinrememberingrecentlylearnedfactsandinabilitytoacquirenewinformation.[27] Subtleproblemswiththeexecutivefunctionsofattentiveness,planning,flexibility,andabstractthinking,orimpairmentsinsemanticmemory(memoryofmeanings,andconceptrelationships)canalsobesymptomaticoftheearlystagesofAlzheimer'sdisease.[27]Apathyanddepressioncanbeseenatthisstage,withapathyremainingasthemostpersistentsymptomthroughoutthecourseofthedisease.[29][30]Mildcognitiveimpairment(MCI)isoftenfoundtobeatransitionalstagebetweennormalaginganddementia.MCIcanpresentwithavarietyofsymptoms,andwhenmemorylossisthepredominantsymptom,itistermedamnesticMCIandisfrequentlyseenasaprodromalstageofAlzheimer'sdisease.[31]AmnesticMCIhasagreaterthan90%likelihoodofbeingassociatedwithAlzheimer's.[32] Earlystage InpeoplewithAlzheimer'sdisease,theincreasingimpairmentoflearningandmemoryeventuallyleadstoadefinitivediagnosis.Inasmallpercentage,difficultieswithlanguage,executivefunctions,perception(agnosia),orexecutionofmovements(apraxia)aremoreprominentthanmemoryproblems.[33]Alzheimer'sdiseasedoesnotaffectallmemorycapacitiesequally.Oldermemoriesoftheperson'slife(episodicmemory),factslearned(semanticmemory),andimplicitmemory(thememoryofthebodyonhowtodothings,suchasusingaforktoeatorhowtodrinkfromaglass)areaffectedtoalesserdegreethannewfactsormemories.[34][35] Languageproblemsaremainlycharacterisedbyashrinkingvocabularyanddecreasedwordfluency,leadingtoageneralimpoverishmentoforalandwrittenlanguage.[33][36]Inthisstage,thepersonwithAlzheimer'sisusuallycapableofcommunicatingbasicideasadequately.[33][36][37]Whileperformingfinemotortaskssuchaswriting,drawing,ordressing,certainmovementcoordinationandplanningdifficulties(apraxia)maybepresent,buttheyarecommonlyunnoticed.[33]Asthediseaseprogresses,peoplewithAlzheimer'sdiseasecanoftencontinuetoperformmanytasksindependently,butmayneedassistanceorsupervisionwiththemostcognitivelydemandingactivities.[33] Middlestage Progressivedeteriorationeventuallyhindersindependence,withsubjectsbeingunabletoperformmostcommonactivitiesofdailyliving.[33]Speechdifficultiesbecomeevidentduetoaninabilitytorecallvocabulary,whichleadstofrequentincorrectwordsubstitutions(paraphasias).Readingandwritingskillsarealsoprogressivelylost.[33][37]ComplexmotorsequencesbecomelesscoordinatedastimepassesandAlzheimer'sdiseaseprogresses,sotheriskoffallingincreases.[33]Duringthisphase,memoryproblemsworsen,andthepersonmayfailtorecognisecloserelatives.[33]Long-termmemory,whichwaspreviouslyintact,becomesimpaired.[33] Behavioralandneuropsychiatricchangesbecomemoreprevalent.Commonmanifestationsarewandering,irritabilityandemotionallability,leadingtocrying,outburstsofunpremeditatedaggression,orresistancetocaregiving.[33]Sundowningcanalsoappear.[38]Approximately30%ofpeoplewithAlzheimer'sdiseasedevelopillusionarymisidentificationsandotherdelusionalsymptoms.[33]Subjectsalsoloseinsightoftheirdiseaseprocessandlimitations(anosognosia).[33]Urinaryincontinencecandevelop.[33]Thesesymptomscreatestressforrelativesandcaregivers,whichcanbereducedbymovingthepersonfromhomecaretootherlong-termcarefacilities.[33][39] Latestage Anormalbrainontheleftandalate-stageAlzheimer'sbrainontheright Duringthefinalstage,knownasthelate-stageorseverestage,thereiscompletedependenceoncaregivers.[13][25][33]Languageisreducedtosimplephrasesorevensinglewords,eventuallyleadingtocompletelossofspeech.[33][37]Despitethelossofverballanguageabilities,peoplecanoftenunderstandandreturnemotionalsignals.Althoughaggressivenesscanstillbepresent,extremeapathyandexhaustionaremuchmorecommonsymptoms.PeoplewithAlzheimer'sdiseasewillultimatelynotbeabletoperformeventhesimplesttasksindependently;musclemassandmobilitydeterioratestothepointwheretheyarebedriddenandunabletofeedthemselves.Thecauseofdeathisusuallyanexternalfactor,suchasinfectionofpressureulcersorpneumonia,notthediseaseitself.[33] Causes Proteinsfailtofunctionnormally.Thisdisruptstheworkofthebraincellsaffectedandtriggersatoxiccascade,ultimatelyleadingtocelldeathandlaterbrainshrinkage.[40] Alzheimer'sdiseaseisbelievedtooccurwhenabnormalamountsofamyloidbeta(Aβ),accumulatingextracellularlyasamyloidplaquesandtauproteins,orintracellularlyasneurofibrillarytangles,forminthebrain,affectingneuronalfunctioningandconnectivity,resultinginaprogressivelossofbrainfunction.[41][42]Thisalteredproteinclearanceabilityisage-related,regulatedbybraincholesterol,[43]andassociatedwithotherneurodegenerativediseases.[44][45] Advancesinbrainimagingtechniquesallowresearcherstoseethedevelopmentandspreadofabnormalamyloidandtauproteinsinthelivingbrain,aswellaschangesinbrainstructureandfunction.[24]Beta-amyloidisafragmentofalargerprotein.Whenthesefragmentsclustertogether,atoxiceffectappearsonneuronsanddisruptcell-to-cellcommunication.Largerdepositscalledamyloidplaquesarethusfurtherformed.[40] Tauproteinsareresponsibleinneuron'sinternalsupportandtransportsystemtocarrynutrientsandotheressentialmaterials.InAlzheimer'sdisease,theshapeoftauproteinsisalteredandthusorganizethemselvesintostructurescalledneurofibrillarytangles.Thetanglesdisruptthetransportsystemandaretoxictocells. ThecauseformostAlzheimer'scasesisstillmostlyunknown,[10]exceptfor1–2%ofcaseswheredeterministicgeneticdifferenceshavebeenidentified.[15]Severalcompetinghypothesesattempttoexplaintheunderlyingcause;thetwopredominanthypothesesaretheamyloidbeta(Aβ)hypothesisandthecholinergichypothesis.[10] Theoldesthypothesis,onwhichmostdrugtherapiesarebased,isthecholinergichypothesis,whichproposesthatAlzheimer'sdiseaseiscausedbyreducedsynthesisoftheneurotransmitteracetylcholine.[10]Thelossofcholinergicneuronsnotedinthelimbicsystemandcerebralcortex,isakeyfeatureintheprogressionofAlzheimer's.[31]The1991amyloidhypothesispostulatedthatextracellularamyloidbeta(Aβ)depositsarethefundamentalcauseofthedisease.[46][47]Supportforthispostulatecomesfromthelocationofthegenefortheamyloidprecursorprotein(APP)onchromosome21,togetherwiththefactthatpeoplewithtrisomy21(Downsyndrome)whohaveanextragenecopyalmostuniversallyexhibitatleasttheearliestsymptomsofAlzheimer'sdiseaseby40 yearsofage.[7]Aspecificisoformofapolipoprotein,APOE4,isamajorgeneticriskfactorforAlzheimer'sdisease.[11]Whileapolipoproteinsenhancethebreakdownofbetaamyloid,someisoformsarenotveryeffectiveatthistask(suchasAPOE4),leadingtoexcessamyloidbuildupinthebrain.[48] Genetic Only1–2%ofAlzheimer'scasesareinherited(autosomaldominant).ThesetypesareknownasearlyonsetfamilialAlzheimer'sdisease,canhaveaveryearlyonset,andafasterrateofprogression.[15]EarlyonsetfamilialAlzheimer'sdiseasecanbeattributedtomutationsinoneofthreegenes:thoseencodingamyloid-betaprecursorprotein(APP)andpresenilinsPSEN1andPSEN2.[32]MostmutationsintheAPPandpresenilingenesincreasetheproductionofasmallproteincalledamyloidbeta(Aβ)42,whichisthemaincomponentofamyloidplaques.[49]SomeofthemutationsmerelyaltertheratiobetweenAβ42andtheothermajorforms—particularlyAβ40—withoutincreasingAβ42levels.[50]TwoothergenesassociatedwithautosomaldominantAlzheimer'sdiseaseareABCA7andSORL1.[51] MostcasesofAlzheimer'sarenotinheritedandaretermedsporadicAlzheimer'sdisease,inwhichenvironmentalandgeneticdifferencesmayactasriskfactors.MostcasesofsporadicAlzheimer'sdiseaseincontrasttofamilialAlzheimer'sdiseasearelate-onsetAlzheimer'sdisease(LOAD)developingaftertheageof65years.Lessthan5%ofsporadicAlzheimer'sdiseasehaveanearlieronset.[15]ThestrongestgeneticriskfactorforsporadicAlzheimer'sdiseaseisAPOEε4.[16]APOEε4isoneoffourallelesofapolipoproteinE(APOE).APOEplaysamajorroleinlipid-bindingproteinsinlipoproteinparticlesandtheepsilon4alleledisruptsthisfunction.[52]Between40and80%ofpeoplewithAlzheimer'sdiseasepossessatleastoneAPOEε4allele.[53]TheAPOEε4alleleincreasestheriskofthediseasebythreetimesinheterozygotesandby15timesinhomozygotes.[54]Likemanyhumandiseases,environmentaleffectsandgeneticmodifiersresultinincompletepenetrance.Forexample,certainNigerianpopulationsdonotshowtherelationshipbetweendoseofAPOEε4andincidenceorage-of-onsetforAlzheimer'sdiseaseseeninotherhumanpopulations.[55][56] AllelesintheTREM2genehavebeenassociatedwitha3to5timeshigherriskofdevelopingAlzheimer'sdisease.[57] AJapanesepedigreeoffamilialAlzheimer'sdiseasewasfoundtobeassociatedwithadeletionmutationofcodon693ofAPP.[58]ThismutationanditsassociationwithAlzheimer'sdiseasewasfirstreportedin2008,[59]andisknownastheOsakamutation.OnlyhomozygoteswiththismutationhaveanincreasedriskofdevelopingAlzheimer'sdisease.ThismutationacceleratesAβoligomerizationbuttheproteinsdonotformtheamyloidfibrilsthataggregateintoamyloidplaques,suggestingthatitistheAβoligomerizationratherthanthefibrilsthatmaybethecauseofthisdisease.MiceexpressingthismutationhavealltheusualpathologiesofAlzheimer'sdisease.[60] Otherhypotheses InAlzheimer'sdisease,changesintauproteinleadtothedisintegrationofmicrotubulesinbraincells. Thetauhypothesisproposesthattauproteinabnormalitiesinitiatethediseasecascade.[47]Inthismodel,hyperphosphorylatedtaubeginstopairwithotherthreadsoftauaspairedhelicalfilaments.Eventually,theyformneurofibrillarytanglesinsidenervecellbodies.[61]Whenthisoccurs,themicrotubulesdisintegrate,destroyingthestructureofthecell'scytoskeletonwhichcollapsestheneuron'stransportsystem.[62] AnumberofstudiesconnectthemisfoldedamyloidbetaandtauproteinsassociatedwiththepathologyofAlzheimer'sdisease,asbringingaboutoxidativestressthatleadstochronicinflammation.[63]Sustainedinflammation(neuroinflammation)isalsoafeatureofotherneurodegenerativediseasesincludingParkinson'sdisease,andALS.[64]Spirocheteinfectionshavealsobeenlinkedtodementia.[10]DNAdamagesaccumulateinADbrains;reactiveoxygenspeciesmaybethemajorsourceofthisDNAdamage.[65] SleepdisturbancesareseenasapossibleriskfactorforinflammationinAlzheimer'sdisease.SleepproblemshavebeenseenasaconsequenceofAlzheimer'sdiseasebutstudiessuggestthattheymayinsteadbeacausalfactor.Sleepdisturbancesarethoughttobelinkedtopersistentinflammation.[66]Thecellularhomeostasisofbiometalssuchasioniccopper,iron,andzincisdisruptedinAlzheimer'sdisease,thoughitremainsunclearwhetherthisisproducedbyorcausesthechangesinproteins.[10][67]SmokingisasignificantAlzheimer'sdiseaseriskfactor.[1]Systemicmarkersoftheinnateimmunesystemareriskfactorsforlate-onsetAlzheimer'sdisease.[68]ExposuretoairpollutionmaybeacontributingfactortothedevelopmentofAlzheimer'sdisease.[10] Onehypothesispositsthatdysfunctionofoligodendrocytesandtheirassociatedmyelinduringagingcontributestoaxondamage,whichthencausesamyloidproductionandtauhyper-phosphorylationasasideeffect.[69][70] Retrogenesisisamedicalhypothesisthatjustasthefetusgoesthroughaprocessofneurodevelopmentbeginningwithneurulationandendingwithmyelination,thebrainsofpeoplewithAlzheimer'sdiseasegothroughareverseneurodegenerationprocessstartingwithdemyelinationanddeathofaxons(whitematter)andendingwiththedeathofgreymatter.[71]Likewisethehypothesisis,thatasinfantsgothroughstatesofcognitivedevelopment,peoplewithAlzheimer'sdiseasegothroughthereverseprocessofprogressivecognitiveimpairment.[72] Theassociationwithceliacdiseaseisunclear,witha2019studyfindingnoincreaseindementiaoverallinthosewithCD,whilea2018reviewfoundanassociationwithseveraltypesofdementiaincludingAlzheimer'sdisease.[73][74] Pathophysiology HistopathologicimagesofAlzheimer'sdisease,intheCA3areaofthehippocampus,showinganamyloidplaque(topright),neurofibrillarytangles(bottomleft),andgranulovacuolardegenerationbodies(bottomcenter) Neuropathology Alzheimer'sdiseaseischaracterisedbylossofneuronsandsynapsesinthecerebralcortexandcertainsubcorticalregions.Thislossresultsingrossatrophyoftheaffectedregions,includingdegenerationinthetemporallobeandparietallobe,andpartsofthefrontalcortexandcingulategyrus.[75]Degenerationisalsopresentinbrainstemnucleiparticularlythelocuscoeruleusinthepons.[76]StudiesusingMRIandPEThavedocumentedreductionsinthesizeofspecificbrainregionsinpeoplewithAlzheimer'sdiseaseastheyprogressedfrommildcognitiveimpairmenttoAlzheimer'sdisease,andincomparisonwithsimilarimagesfromhealthyolderadults.[77][78] BothAβplaquesandneurofibrillarytanglesareclearlyvisiblebymicroscopyinbrainsofthosewithAlzheimer'sdisease,[79]especiallyinthehippocampus.[80]However,Alzheimer'sdiseasemayoccurwithoutneurofibrillarytanglesintheneocortex.[81]Plaquesaredense,mostlyinsolubledepositsofbeta-amyloidpeptideandcellularmaterialoutsideandaroundneurons.Tangles(neurofibrillarytangles)areaggregatesofthemicrotubule-associatedproteintauwhichhasbecomehyperphosphorylatedandaccumulateinsidethecellsthemselves.Althoughmanyolderindividualsdevelopsomeplaquesandtanglesasaconsequenceofaging,thebrainsofpeoplewithAlzheimer'sdiseasehaveagreaternumberoftheminspecificbrainregionssuchasthetemporallobe.[82]LewybodiesarenotrareinthebrainsofpeoplewithAlzheimer'sdisease.[83] Biochemistry Mainarticle:BiochemistryofAlzheimer'sdisease EnzymesactontheAPP(amyloid-betaprecursorprotein)andcutitintofragments.Thebeta-amyloidfragmentiscrucialintheformationofamyloidplaquesinAlzheimer'sdisease. Alzheimer'sdiseasehasbeenidentifiedasaproteinmisfoldingdisease,aproteopathy,causedbytheaccumulationofabnormallyfoldedamyloidbetaproteinintoamyloidplaques,andtauproteinintoneurofibrillarytanglesinthebrain.[84]Plaquesaremadeupofsmallpeptides,39–43 aminoacidsinlength,calledamyloidbeta(Aβ).Amyloidbetaisafragmentfromthelargeramyloid-betaprecursorprotein(APP)atransmembraneproteinthatpenetratestheneuron'smembrane.APPiscriticaltoneurongrowth,survival,andpost-injuryrepair.[85][86]InAlzheimer'sdisease,gammasecretaseandbetasecretaseacttogetherinaproteolyticprocesswhichcausesAPPtobedividedintosmallerfragments.[87]Oneofthesefragmentsgivesrisetofibrilsofamyloidbeta,whichthenformclumpsthatdepositoutsideneuronsindenseformationsknownasamyloidplaques.[79][88] Alzheimer'sdiseaseisalsoconsideredatauopathyduetoabnormalaggregationofthetauprotein.Everyneuronhasacytoskeleton,aninternalsupportstructurepartlymadeupofstructurescalledmicrotubules.Thesemicrotubulesactliketracks,guidingnutrientsandmoleculesfromthebodyofthecelltotheendsoftheaxonandback.Aproteincalledtaustabilisesthemicrotubuleswhenphosphorylated,andisthereforecalledamicrotubule-associatedprotein.InAlzheimer'sdisease,tauundergoeschemicalchanges,becominghyperphosphorylated;itthenbeginstopairwithotherthreads,creatingneurofibrillarytanglesanddisintegratingtheneuron'stransportsystem.[89]Pathogenictaucanalsocauseneuronaldeaththroughtransposableelementdysregulation.[90] Diseasemechanism Exactlyhowdisturbancesofproductionandaggregationofthebeta-amyloidpeptidegiverisetothepathologyofAlzheimer'sdiseaseisnotknown.[91][92]Theamyloidhypothesistraditionallypointstotheaccumulationofbeta-amyloidpeptidesasthecentraleventtriggeringneurondegeneration.Accumulationofaggregatedamyloidfibrils,whicharebelievedtobethetoxicformoftheproteinresponsiblefordisruptingthecell'scalciumionhomeostasis,inducesprogrammedcelldeath(apoptosis).[93]ItisalsoknownthatAβselectivelybuildsupinthemitochondriainthecellsofAlzheimer's-affectedbrains,anditalsoinhibitscertainenzymefunctionsandtheutilisationofglucosebyneurons.[94] VariousinflammatoryprocessesandcytokinesmayalsohavearoleinthepathologyofAlzheimer'sdisease.Inflammationisageneralmarkeroftissuedamageinanydisease,andmaybeeithersecondarytotissuedamageinAlzheimer'sdiseaseoramarkerofanimmunologicalresponse.[95]Thereisincreasingevidenceofastronginteractionbetweentheneuronsandtheimmunologicalmechanismsinthebrain.Obesityandsystemicinflammationmayinterferewithimmunologicalprocesseswhichpromotediseaseprogression.[96] Alterationsinthedistributionofdifferentneurotrophicfactorsandintheexpressionoftheirreceptorssuchasthebrain-derivedneurotrophicfactor(BDNF)havebeendescribedinAlzheimer'sdisease.[97][98] Diagnosis Seealso:Early-onsetAlzheimer'sdisease§ Diagnosis PETscanofthebrainofapersonwithAlzheimer'sdiseaseshowingalossoffunctioninthetemporallobe Alzheimer'sdiseaseisusuallydiagnosedbasedontheperson'smedicalhistory,historyfromrelatives,andbehavioralobservations.Thepresenceofcharacteristicneurologicalandneuropsychologicalfeaturesandtheabsenceofalternativeconditionssupportsthediagnosis.[99][100]Advancedmedicalimagingwithcomputedtomography(CT)ormagneticresonanceimaging(MRI),andwithsingle-photonemissioncomputedtomography(SPECT)orpositronemissiontomography(PET),canbeusedtohelpexcludeothercerebralpathologyorsubtypesofdementia.[101]Moreover,itmaypredictconversionfromprodromalstages(mildcognitiveimpairment)toAlzheimer'sdisease.[102]FDA-approvedradiopharmaceuticaldiagnosticagentsusedinPETforAlzheimer'sdiseaseareflorbetapir(2012),flutemetamol(2013),florbetaben(2014),andflortaucipir(2020).[103]BecausemanyinsurancecompaniesintheUnitedStatesdonotcoverthisprocedure,itsuseinclinicalpracticeislargelylimitedtoclinicaltrialsasof2018[update].[104] Assessmentofintellectualfunctioningincludingmemorytestingcanfurthercharacterisethestateofthedisease.[1]Medicalorganizationshavecreateddiagnosticcriteriatoeaseandstandardisethediagnosticprocessforpractisingphysicians.Definitivediagnosiscanonlybeconfirmedwithpost-mortemevaluationswhenbrainmaterialisavailableandcanbeexaminedhistologicallyforsenileplaquesandneurofibrillarytangles.[104][105] Criteria TherearethreesetsofcriteriafortheclinicaldiagnosesofthespectrumofAlzheimer'sdisease:the2013fiftheditionoftheDiagnosticandStatisticalManualofMentalDisorders(DSM-5);theNationalInstituteonAging-Alzheimer'sAssociation(NIA-AA)definitionasrevisedin2011;andtheInternationalWorkingGroupcriteriaasrevisedin2010.[32][104]Threebroadtimeperiods,whichcanspandecades,definetheprogressionofAlzheimer'sdiseasefromthepreclinicalphase,tomildcognitiveimpairment(MCI),followedbyAlzheimer'sdiseasedementia.[106] EightintellectualdomainsaremostcommonlyimpairedinAD—memory,language,perceptualskills,attention,motorskills,orientation,problemsolvingandexecutivefunctionalabilities,aslistedinthefourthtextrevisionoftheDSM(DSM-IV-TR).[107] TheDSM-5definescriteriaforprobableorpossibleAlzheimer'sforbothmajorandmildneurocognitivedisorder.[108][109][110]MajorormildneurocognitivedisordermustbepresentalongwithatleastonecognitivedeficitforadiagnosisofeitherprobableorpossibleAD.[108][111]FormajorneurocognitivedisorderduetoAlzheimer'sdisease,probableAlzheimer'sdiseasecanbediagnosediftheindividualhasgeneticevidenceofAlzheimer's[112]oriftwoormoreacquiredcognitivedeficits,andafunctionaldisabilitythatisnotfromanotherdisorder,arepresent.[113]Otherwise,possibleAlzheimer'sdiseasecanbediagnosedasthediagnosisfollowsanatypicalroute.[114]FormildneurocognitivedisorderduetoAlzheimer's,probableAlzheimer'sdiseasecanbediagnosedifthereisgeneticevidence,whereaspossibleAlzheimer'sdiseasecanbemetifallofthefollowingarepresent:nogeneticevidence,declineinbothlearningandmemory,twoormorecognitivedeficits,andafunctionaldisabilitynotfromanotherdisorder.[108][115] TheNIA-AAcriteriaareusedmainlyinresearchratherthaninclinicalassessments.[116]TheydefineAlzheimer'sdiseasethroughthreemajorstages:preclinical,mildcognitiveimpairment(MCI),andAlzheimer'sdementia.[117][118]Diagnosisinthepreclinicalstageiscomplexandfocusesonasymptomaticindividuals;[118][119]thelattertwostagesdescribeindividualsexperiencingsymptoms.[118]ThecoreclinicalcriteriaforMCIisusedalongwithidentificationofbiomarkers,[120]predominantlythoseforneuronalinjury(mainlytau-related)andamyloidbetadeposition.[116][118]Thecoreclinicalcriteriaitselfrestsonthepresenceofcognitiveimpairment[118]withoutthepresenceofcomorbidities.[121][122]ThethirdstageisdividedintoprobableandpossibleAlzheimer'sdiseasedementia.[122]InprobableAlzheimer'sdiseasedementiathereissteadyimpairmentofcognitionovertimeandamemory-relatedornon-memory-relatedcognitivedysfunction.[122]InpossibleAlzheimer'sdiseasedementia,anothercausaldiseasesuchascerebrovasculardiseaseispresent.[122] Techniques CognitivetestssuchastheMini–MentalStateExamination(MMSE)canhelpinthediagnosisofAlzheimer'sdisease.Inthistestinstructionsaregiventocopydrawingsliketheoneshown,remembersomewords,read,andsubtractnumbersserially. NeuropsychologicaltestsincludingcognitivetestssuchastheMini–MentalStateExamination(MMSE),theMontrealCognitiveAssessment(MoCA)andtheMini-CogarewidelyusedtoaidindiagnosisofthecognitiveimpairmentsinAD.[123]Thesetestsmaynotalwaysbeaccurate,astheylacksensitivitytomildcognitiveimpairment,andcanbebiasedbylanguageorattentionproblems;[123]morecomprehensivetestarraysarenecessaryforhighreliabilityofresults,particularlyintheearlieststagesofthedisease.[124][125] FurtherneurologicalexaminationsarecrucialinthedifferentialdiagnosisofAlzheimer'sdiseaseandotherdiseases.[26]Interviewswithfamilymembersareusedinassessment;caregiverscansupplyimportantinformationondailylivingabilitiesandonthedecreaseintheperson'smentalfunction.[126]Acaregiver'sviewpointisparticularlyimportant,sinceapersonwithAlzheimer'sdiseaseiscommonlyunawareoftheirdeficits.[127]Manytimes,familieshavedifficultiesinthedetectionofinitialdementiasymptomsandmaynotcommunicateaccurateinformationtoaphysician.[128] Supplementaltestingcanruleoutotherpotentiallytreatablediagnosesandhelpavoidmisdiagnoses.[129]Commonsupplementaltestsincludebloodtests,thyroidfunctiontests,aswellasteststoassessvitaminB12levels,ruleoutneurosyphilisandruleoutmetabolicproblems(includingtestsforkidneyfunction,electrolytelevelsandfordiabetes).[129]MRIorCTscansmightalsobeusedtoruleoutotherpotentialcausesofthesymptoms–includingtumorsorstrokes.[123]Deliriumanddepressioncanbecommonamongindividualsandareimportanttoruleout.[130] Psychologicaltestsfordepressionareused,sincedepressioncaneitherbeconcurrentwithAlzheimer'sdisease(seeDepressionofAlzheimerdisease),anearlysignofcognitiveimpairment,[131]oreventhecause.[132][133] Duetolowaccuracy,theC-PIB-PETscanisnotrecommendedasanearlydiagnostictoolorforpredictingthedevelopmentofAlzheimer'sdiseasewhenpeopleshowsignsofmildcognitiveimpairment(MCI).[134]Theuseof18F-FDGPETscans,asasingletest,toidentifypeoplewhomaydevelopAlzheimer'sdiseaseisnotsupportedbyevidence.[135] Prevention IntellectualactivitiessuchasplayingchessorregularsocialinteractionhavebeenlinkedtoareducedriskofAlzheimer'sdiseaseinepidemiologicalstudies,althoughnocausalrelationshiphasbeenfound. Therearenodisease-modifyingtreatmentsavailabletocureAlzheimer'sdiseaseandbecauseofthis,ADresearchhasfocusedoninterventionstopreventtheonsetandprogression.[136]ThereisnoevidencethatsupportsanyparticularmeasureinpreventingAlzheimer's,[1]andstudiesofmeasurestopreventtheonsetorprogressionhaveproducedinconsistentresults.Epidemiologicalstudieshaveproposedrelationshipsbetweenanindividual'slikelihoodofdevelopingADandmodifiablefactors,suchasmedications,lifestyle,anddiet.TherearesomechallengesindeterminingwhetherinterventionsforAlzheimer'sdiseaseactasaprimarypreventionmethod,preventingthediseaseitself,orasecondarypreventionmethod,identifyingtheearlystagesofthedisease.[17]Thesechallengesincludedurationofintervention,differentstagesofdiseaseatwhichinterventionbegins,andlackofstandardizationofinclusioncriteriaregardingbiomarkersspecificforAlzheimer'sdisease.[17]FurtherresearchisneededtodeterminefactorsthatcanhelppreventAlzheimer'sdisease.[17] Medication Cardiovascularriskfactors,suchashypercholesterolaemia,hypertension,diabetes,andsmoking,areassociatedwithahigherriskofonsetandworsenedcourseofAD.[137][138]TheuseofstatinstolowercholesterolmaybeofbenefitinAlzheimer's.[139]Antihypertensiveandantidiabeticmedicationsinindividualswithoutovertcognitiveimpairmentmaydecreasetheriskofdementiabyinfluencingcerebrovascularpathology.[1][140]MoreresearchisneededtoexaminetherelationshipwithAlzheimer'sdiseasespecifically;clarificationofthedirectrolemedicationsplayversusotherconcurrentlifestylechanges(diet,exercise,smoking)isneeded.[1] DepressionisassociatedwithanincreasedriskforAlzheimer'sdisease;managementwithantidepressantsmayprovideapreventativemeasure.[141] Historically,long-termusageofnon-steroidalanti-inflammatorydrugs(NSAIDs)werethoughttobeassociatedwithareducedlikelihoodofdevelopingAlzheimer'sdiseaseasitreducesinflammation;however,NSAIDsdonotappeartobeusefulasatreatment.[104]Additionally,becausewomenhaveahigherincidenceofAlzheimer'sdiseasethanmen,itwasoncethoughtthatestrogendeficiencyduringmenopausewasariskfactor.However,thereisalackofevidencetoshowthathormonereplacementtherapy(HRT)inmenopausedecreasesriskofcognitivedecline.[142] Lifestyle Furtherinformation:Neurobiologicaleffectsofphysicalexercise Certainlifestyleactivities,suchasphysicalandcognitiveexercises,highereducationandoccupationalattainment,cigarettesmoking,stress,sleep,andthemanagementofothercomorbiditiesincluding,diabetesandhypertensionmayaffecttheriskofdevelopingAlzheimer's.[141] Physicalexerciseisassociatedwithadecreasedrateofdementia,[143]andiseffectiveinreducingsymptomseverityinthosewithAD.[144]Memoryandcognitivefunctionscanbeimprovedwithaerobicexercisesincludingbriskwalkingthreetimesweeklyforfortyminutes.[145]Itmayalsoinduceneuroplasticityofthebrain.[146]Participatinginmentalexercises,suchasreading,crosswordpuzzles,andchesshaveshownapotentialtobepreventative.[141] Highereducationandoccupationalattainment,andparticipationinleisureactivities,contributetoareducedriskofdevelopingAlzheimer's,[147]orofdelayingtheonsetofsymptoms.Thisiscompatiblewiththecognitivereservetheory,whichstatesthatsomelifeexperiencesresultinmoreefficientneuralfunctioningprovidingtheindividualacognitivereservethatdelaystheonsetofdementiamanifestations.[147]EducationdelaystheonsetofAlzheimer'sdiseasesyndromewithoutchangingthedurationofthedisease.[148] CessationinsmokingmayreduceriskofdevelopingAlzheimer's'disease,specificallyinthosewhocarryAPOEɛ4allele.[149][141]TheincreasedoxidativestresscausedbysmokingresultsindownstreaminflammatoryorneurodegenerativeprocessesthatmayincreaseriskofdevelopingAD.[150]Avoidanceofsmoking,counselingandpharmacotherapiestoquitsmokingareused,andavoidanceofenvironmentaltobaccosmokeisrecommended.[141] Alzheimer'sdiseaseisassociatedwithsleepdisordersbutthepreciserelationshipisunclear.[151][152]Itwasoncethoughtthataspeoplegetolder,theriskofdevelopingsleepdisordersandADindependentlyincrease,butresearchisexaminingwhethersleepdisordersmayincreasetheprevalenceofAD.[151]Onetheoryisthatthemechanismstoincreaseclearanceoftoxicsubstances,includingAβ,areactiveduringsleep.[151][153]Withdecreasedsleep,apersonisincreasingAβproductionanddecreasingAβclearance,resultinginAβaccumulation.[154][151][152]Receivingadequatesleep(approximately7–8hours)everynighthasbecomeapotentiallifestyleinterventiontopreventthedevelopmentofAD.[141] StressisariskfactorforthedevelopmentofAlzheimer's.[141]ThemechanismbywhichstresspredisposessomeonetodevelopmentofAlzheimer'sisunclear,butitissuggestedthatlifetimestressorsmayaffectaperson'sepigenome,leadingtoanoverexpressionorunderexpressionofspecificgenes.[155]AlthoughtherelationshipofstressandAlzheimer'sisunclear,strategiestoreducestressandrelaxthemindmaybehelpfulstrategiesinpreventingtheprogressionorAlzheimer'sdisease.[156]Meditation,forinstance,isahelpfullifestylechangetosupportcognitionandwell-being,thoughfurtherresearchisneededtoassesslong-termeffects.[146] Management ThereisnocureforAlzheimer'sdisease;availabletreatmentsofferrelativelysmallsymptomaticbenefitsbutremainpalliativeinnature.[10][157]Treatmentscanbedividedintopharmaceutical,psychosocial,andcaregiving. Pharmaceutical Thissectionneedstobeupdated.Pleasehelpupdatethisarticletoreflectrecenteventsornewlyavailableinformation.(February2022) Three-dimensionalmolecularmodelofdonepezil,anacetylcholinesteraseinhibitorusedinthetreatmentofAlzheimer'sdiseasesymptoms Molecularstructureofmemantine,amedicationapprovedforadvancedAlzheimer'sdiseasesymptoms MedicationsusedtotreatthecognitiveproblemsofAlzheimer'sdiseaseinclude:fouracetylcholinesteraseinhibitors(tacrine,rivastigmine,galantamine,anddonepezil)andmemantine,anNMDAreceptorantagonist.TheacetylcholinesteraseinhibitorsareintendedforthosewithmildtosevereAlzheimer's,whereasmemantineisintendedforthosewithmoderateorsevereAlzheimer'sdisease.[104]Thebenefitfromtheiruseissmall.[158][159][160][11] Reductionintheactivityofthecholinergicneuronsisawell-knownfeatureofAlzheimer'sdisease.[161]Acetylcholinesteraseinhibitorsareemployedtoreducetherateatwhichacetylcholine(ACh)isbrokendown,therebyincreasingtheconcentrationofAChinthebrainandcombatingthelossofAChcausedbythedeathofcholinergicneurons.[162]ThereisevidencefortheefficacyofthesemedicationsinmildtomoderateAlzheimer'sdisease,[163][158]andsomeevidencefortheiruseintheadvancedstage.[158]TheuseofthesedrugsinmildcognitiveimpairmenthasnotshownanyeffectinadelayoftheonsetofAlzheimer'sdisease.[164]Themostcommonsideeffectsarenauseaandvomiting,bothofwhicharelinkedtocholinergicexcess.Thesesideeffectsariseinapproximately10–20%ofusers,aremildtomoderateinseverity,andcanbemanagedbyslowlyadjustingmedicationdoses.[165]Lesscommonsecondaryeffectsincludemusclecramps,decreasedheartrate(bradycardia),decreasedappetiteandweight,andincreasedgastricacidproduction.[163] Glutamateisanexcitatoryneurotransmitterofthenervoussystem,althoughexcessiveamountsinthebraincanleadtocelldeaththroughaprocesscalledexcitotoxicitywhichconsistsoftheoverstimulationofglutamatereceptors.ExcitotoxicityoccursnotonlyinAlzheimer'sdisease,butalsoinotherneurologicaldiseasessuchasParkinson'sdiseaseandmultiplesclerosis.[166]MemantineisanoncompetitiveNMDAreceptorantagonistfirstusedasananti-influenzaagent.ItactsontheglutamatergicsystembyblockingNMDAreceptorsandinhibitingtheiroverstimulationbyglutamate.[166][167]MemantinehasbeenshowntohaveasmallbenefitinthetreatmentofmoderatetosevereAlzheimer'sdisease.[168]Reportedadverseeventswithmemantineareinfrequentandmild,includinghallucinations,confusion,dizziness,headacheandfatigue.[169][170]Thecombinationofmemantineanddonepezil[171]hasbeenshowntobe"ofstatisticallysignificantbutclinicallymarginaleffectiveness".[172] AnextractofGinkgobilobaknownasEGb761hasbeenwidelyusedfortreatingAlzheimer'sandotherneuropsychiatricdisorders.[173]ItsuseisapprovedthroughoutEurope.[174]TheWorldFederationofBiologicalPsychiatryguidelineslistsEGb761withthesameweightofevidence(levelB)giventoacetylcholinesteraseinhibitors,andmemantine.EGb761istheonlyonethatshowedimprovementofsymptomsinbothAlzheimer'sdiseaseandvasculardementia.EGb761isseenasbeingabletoplayanimportantroleeitheronitsownorasanadd-onparticularlywhenothertherapiesproveineffective.[173]EGb761isseentobeneuroprotective;itisafreeradicalscavenger,improvesmitochondrialfunction,andmodulatesserotoninanddopaminelevels.Manystudiesofitsuseinmildtomoderatedementiahaveshownittosignificantlyimprovecognitivefunction,activitiesofdailyliving,andneuropsychiatricsymptoms.However,itsusehasnotbeenshowntopreventtheprogressiontodementia.[173] AtypicalantipsychoticsaremodestlyusefulinreducingaggressionandpsychosisinpeoplewithAlzheimer'sdisease,buttheiradvantagesareoffsetbyseriousadverseeffects,suchasstroke,movementdifficultiesorcognitivedecline.[175]Whenusedinthelong-term,theyhavebeenshowntoassociatewithincreasedmortality.[176]Stoppingantipsychoticuseinthisgroupofpeopleappearstobesafe.[177] Psychosocial Psychosocialinterventionsareusedasanadjuncttopharmaceuticaltreatmentandcanbeclassifiedwithinbehavior-,emotion-,cognition-orstimulation-orientedapproaches.[needsupdate][178] Behavioralinterventionsattempttoidentifyandreducetheantecedentsandconsequencesofproblembehaviors.Thisapproachhasnotshownsuccessinimprovingoverallfunctioning,[179]butcanhelptoreducesomespecificproblembehaviors,suchasincontinence.[180]Thereisalackofhighqualitydataontheeffectivenessofthesetechniquesinotherbehaviorproblemssuchaswandering.[181][182]Musictherapyiseffectiveinreducingbehavioralandpsychologicalsymptoms.[183] Emotion-orientedinterventionsincludereminiscencetherapy,validationtherapy,supportivepsychotherapy,sensoryintegration,alsocalledsnoezelen,andsimulatedpresencetherapy.ACochranereviewhasfoundnoevidencethatthisiseffective.[184]Reminiscencetherapy(RT)involvesthediscussionofpastexperiencesindividuallyoringroup,manytimeswiththeaidofphotographs,householditems,musicandsoundrecordings,orotherfamiliaritemsfromthepast.A2018reviewoftheeffectivenessofRTfoundthateffectswereinconsistent,smallinsizeandofdoubtfulclinicalsignificance,andvariedbysetting.[185]Simulatedpresencetherapy(SPT)isbasedonattachmenttheoriesandinvolvesplayingarecordingwithvoicesoftheclosestrelativesofthepersonwithAlzheimer'sdisease.ThereispartialevidenceindicatingthatSPTmayreducechallengingbehaviors.[186] Theaimofcognition-orientedtreatments,whichincluderealityorientationandcognitiveretraining,isthereductionofcognitivedeficits.Realityorientationconsistsofthepresentationofinformationabouttime,place,orpersontoeasetheunderstandingofthepersonaboutitssurroundingsandhisorherplaceinthem.Ontheotherhand,cognitiveretrainingtriestoimproveimpairedcapacitiesbyexercisingmentalabilities.Bothhaveshownsomeefficacyimprovingcognitivecapacities.[187] Stimulation-orientedtreatmentsincludeart,musicandpettherapies,exercise,andanyotherkindofrecreationalactivities.Stimulationhasmodestsupportforimprovingbehavior,mood,and,toalesserextent,function.Nevertheless,asimportantastheseeffectsare,themainsupportfortheuseofstimulationtherapiesisthechangeintheperson'sroutine.[178] Caregiving Furtherinformation:CaringforpeoplewithdementiaandPalliativecare SinceAlzheimer'shasnocureanditgraduallyrenderspeopleincapableoftendingtotheirownneeds,caregivingisessentiallythetreatmentandmustbecarefullymanagedoverthecourseofthedisease. Duringtheearlyandmoderatestages,modificationstothelivingenvironmentandlifestylecanincreasesafetyandreducecaretakerburden.[188][189]Examplesofsuchmodificationsaretheadherencetosimplifiedroutines,theplacingofsafetylocks,thelabelingofhouseholditemstocuethepersonwiththediseaseortheuseofmodifieddailylifeobjects.[178][190][191]Ifeatingbecomesproblematic,foodwillneedtobepreparedinsmallerpiecesorevenpuréed.[192]Whenswallowingdifficultiesarise,theuseoffeedingtubesmayberequired.Insuchcases,themedicalefficacyandethicsofcontinuingfeedingisanimportantconsiderationofthecaregiversandfamilymembers.[193][194]Theuseofphysicalrestraintsisrarelyindicatedinanystageofthedisease,althoughtherearesituationswhentheyarenecessarytopreventharmtothepersonwithAlzheimer'sdiseaseortheircaregivers.[178] Duringthefinalstagesofthedisease,treatmentiscentredonrelievingdiscomfortuntildeath,oftenwiththehelpofhospice.[195] Diet DietmaybeamodifiableriskfactorforthedevelopmentofAlzheimer'sdisease.TheMediterraneandiet,andtheDASHdietarebothassociatedwithlesscognitivedecline.AdifferentapproachhasbeentoincorporateelementsofbothofthesedietsintooneknownastheMINDdiet.[196]Studiesofindividualdietarycomponents,mineralsandsupplementsareconflictingastowhethertheypreventADorcognitivedecline.[196][197][198] Prognosis TheearlystagesofAlzheimer'sdiseasearedifficulttodiagnose.Adefinitivediagnosisisusuallymadeoncecognitiveimpairmentcompromisesdailylivingactivities,althoughthepersonmaystillbelivingindependently.Thesymptomswillprogressfrommildcognitiveproblems,suchasmemorylossthroughincreasingstagesofcognitiveandnon-cognitivedisturbances,eliminatinganypossibilityofindependentliving,especiallyinthelatestagesofthedisease.[33] LifeexpectancyofpeoplewithAlzheimer'sdiseaseisreduced.[199]Thenormallifeexpectancyfor60to70yearsoldis23to15years;for90yearsolditis4.5years.[200]FollowingAlzheimer'sdiseasediagnosisitrangesfrom7to10yearsforthoseintheir60sandearly70s(alossof13to8years),toonlyabout3yearsorless(alossof1.5years)forthoseintheir90s.[199] Fewerthan3%ofpeoplelivemorethanfourteenyears.[201]Diseasefeaturessignificantlyassociatedwithreducedsurvivalareanincreasedseverityofcognitiveimpairment,decreasedfunctionallevel,historyoffalls,anddisturbancesintheneurologicalexamination.Othercoincidentdiseasessuchasheartproblems,diabetes,orhistoryofalcoholabusearealsorelatedwithshortenedsurvival.[202][203][204]Whiletheearliertheageatonsetthehigherthetotalsurvivalyears,lifeexpectancyisparticularlyreducedwhencomparedtothehealthypopulationamongthosewhoareyounger.[205]Menhavealessfavourablesurvivalprognosisthanwomen.[201][3] PneumoniaanddehydrationarethemostfrequentimmediatecausesofdeathbroughtbyAlzheimer'sdisease,whilecancerisalessfrequentcauseofdeaththaninthegeneralpopulation.[3] Epidemiology Twomainmeasuresareusedinepidemiologicalstudies:incidenceandprevalence.Incidenceisthenumberofnewcasesperunitofperson-timeatrisk(usuallynumberofnewcasesperthousandperson-years);whileprevalenceisthetotalnumberofcasesofthediseaseinthepopulationatanygiventime. Deathspermillionpersonsin2012duetodementiasincludingAlzheimer'sdisease  0–4  5–8  9–10  11–13  14–17  18–24  25–45  46–114  115–375  376–1266 Regardingincidence,cohortlongitudinalstudies(studieswhereadisease-freepopulationisfollowedovertheyears)provideratesbetween10and15perthousandperson-yearsforalldementiasand5–8forAlzheimer'sdisease,[206][207]whichmeansthathalfofnewdementiacaseseachyearareAlzheimer'sdisease.Advancingageisaprimaryriskfactorforthediseaseandincidenceratesarenotequalforallages:every5yearsaftertheageof65,theriskofacquiringthediseaseapproximatelydoubles,increasingfrom3toasmuchas69perthousandpersonyears.[206][207]FemaleswithAlzheimer'sdiseasearemorecommonthanmales,butthisdifferenceislikelyduetowomen's'longerlifespans.Whenadjustedforage,bothsexesareaffectedbyAlzheimer'satequalrates.[11]IntheUnitedStates,theriskofdyingfromAlzheimer'sdiseasein2010was26%higheramongthenon-Hispanicwhitepopulationthanamongthenon-Hispanicblackpopulation,andtheHispanicpopulationhada30%lowerriskthanthenon-Hispanicwhitepopulation.[208] TheprevalenceofAlzheimer'sdiseaseinpopulationsisdependentuponfactorsincludingincidenceandsurvival.SincetheincidenceofAlzheimer'sdiseaseincreaseswithage,prevalencedependsonthemeanageofthepopulationforwhichprevalenceisgiven.IntheUnitedStatesin2020,Alzheimer'sdementiaprevalencewasestimatedtobe5.3%forthoseinthe60–74agegroup,withtherateincreasingto13.8%inthe74–84groupandto34.6%inthosegreaterthan85.[209]Prevalenceratesinsomelessdevelopedregionsaroundtheglobearelower.[210][211]Astheincidenceandprevalencearesteadilyincreasing,theprevalenceitselfisprojectedtotripleby2050.[clarificationneeded][212]Asof2020,50millionpeoplegloballyhaveAD,withthisnumberexpectedtoincreaseto152millionby2050.[10] History AloisAlzheimer'spatientAugusteDeterin1902.HerswasthefirstdescribedcaseofwhatbecameknownasAlzheimer'sdisease. TheancientGreekandRomanphilosophersandphysiciansassociatedoldagewithincreasingdementia.[23]Itwasnotuntil1901thatGermanpsychiatristAloisAlzheimeridentifiedthefirstcaseofwhatbecameknownasAlzheimer'sdisease,namedafterhim,inafifty-year-oldwomanhecalledAugusteD.Hefollowedhercaseuntilshediedin1906whenhefirstreportedpubliclyonit.[213]Duringthenextfiveyears,elevensimilarcaseswerereportedinthemedicalliterature,someofthemalreadyusingthetermAlzheimer'sdisease.[23]ThediseasewasfirstdescribedasadistinctivediseasebyEmilKraepelinaftersuppressingsomeoftheclinical(delusionsandhallucinations)andpathologicalfeatures(arterioscleroticchanges)containedintheoriginalreportofAugusteD.[214]HeincludedAlzheimer'sdisease,alsonamedpreseniledementiabyKraepelin,asasubtypeofseniledementiaintheeightheditionofhisTextbookofPsychiatry,publishedon15July,1910.[215] Formostofthe20thcentury,thediagnosisofAlzheimer'sdiseasewasreservedforindividualsbetweentheagesof45and65whodevelopedsymptomsofdementia.Theterminologychangedafter1977whenaconferenceonAlzheimer'sdiseaseconcludedthattheclinicalandpathologicalmanifestationsofpresenileandseniledementiawerealmostidentical,althoughtheauthorsalsoaddedthatthisdidnotruleoutthepossibilitythattheyhaddifferentcauses.[216]ThiseventuallyledtothediagnosisofAlzheimer'sdiseaseindependentofage.[217]ThetermseniledementiaoftheAlzheimertype(SDAT)wasusedforatimetodescribetheconditioninthoseover65,withclassicalAlzheimer'sdiseasebeingusedtodescribethosewhowereyounger.Eventually,thetermAlzheimer'sdiseasewasformallyadoptedinmedicalnomenclaturetodescribeindividualsofallageswithacharacteristiccommonsymptompattern,diseasecourse,andneuropathology.[218] TheNationalInstituteofNeurologicalandCommunicativeDisordersandStroke(NINCDS)andtheAlzheimer'sDiseaseandRelatedDisordersAssociation(ADRDA,nowknownastheAlzheimer'sAssociation)establishedthemostcommonlyusedNINCDS-ADRDAAlzheimer'sCriteriafordiagnosisin1984,[219]extensivelyupdatedin2007.[220][129]Thesecriteriarequirethatthepresenceofcognitiveimpairment,andasuspecteddementiasyndrome,beconfirmedbyneuropsychologicaltestingforaclinicaldiagnosisofpossibleorprobableAlzheimer'sdisease.Ahistopathologicconfirmationincludingamicroscopicexaminationofbraintissueisrequiredforadefinitivediagnosis.Goodstatisticalreliabilityandvalidityhavebeenshownbetweenthediagnosticcriteriaanddefinitivehistopathologicalconfirmation.[221] Societyandculture Seealso:Alzheimer'sdiseaseorganizations Socialcosts Dementia,andspecificallyAlzheimer'sdisease,maybeamongthemostcostlydiseasesforsocietiesworldwide.[222]Aspopulationsage,thesecostswillprobablyincreaseandbecomeanimportantsocialproblemandeconomicburden.[223]CostsassociatedwithADincludedirectandindirectmedicalcosts,whichvarybetweencountriesdependingonsocialcareforapersonwithAD.[222][224][225]Directcostsincludedoctorvisits,hospitalcare,medicaltreatments,nursinghomecare,specializedequipment,andhouseholdexpenses.[222][223]Indirectcostsincludethecostofinformalcareandthelossinproductivityofinformalcaregivers.[223] IntheUnitedStatesasof2019[update],informal(family)careisestimatedtoconstitutenearlythree-fourthsofcaregivingforpeoplewithADatacostofUS$234billionperyearandapproximately18.5billionhoursofcare.[222]ThecosttosocietyworldwidetocareforindividualswithADisprojectedtoincreasenearlyten-fold,andreachaboutUS$9.1trillionby2050.[224] Costsforthosewithmoreseveredementiaorbehavioraldisturbancesarehigherandarerelatedtotheadditionalcaregivingtimetoprovidephysicalcare.[225] Caregivingburden Furtherinformation:Caregivinganddementia Thissectionneedstobeupdated.Pleasehelpupdatethisarticletoreflectrecenteventsornewlyavailableinformation.(February2022) Theroleofthemaincaregiverisoftentakenbythespouseoracloserelative.[226]Alzheimer'sdiseaseisknownforplacingagreatburdenoncaregiverswhichincludessocial,psychological,physical,oreconomicaspects.[18][227][228]HomecareisusuallypreferredbypeoplewithAlzheimer'sdiseaseandtheirfamilies.[229]Thisoptionalsodelaysoreliminatestheneedformoreprofessionalandcostlylevelsofcare.[229][230]Nevertheless,two-thirdsofnursinghomeresidentshavedementias.[178] Dementiacaregiversaresubjecttohighratesofphysicalandmentaldisorders.[231]Factorsassociatedwithgreaterpsychosocialproblemsoftheprimarycaregiversincludehavinganaffectedpersonathome,thecarerbeingaspouse,demandingbehaviorsofthecaredpersonsuchasdepression,behavioraldisturbances,hallucinations,sleepproblemsorwalkingdisruptionsandsocialisolation.[232][233]Regardingeconomicproblems,familycaregiversoftengiveuptimefromworktospend47 hoursperweekonaveragewiththepersonwithAlzheimer'sdisease,whilethecostsofcaringforthemarehigh.DirectandindirectcostsofcaringforsomebodywithAlzheimer'saveragebetween$18,000and$77,500peryearintheUnitedStates,dependingonthestudy.[234][226] Cognitivebehavioraltherapyandtheteachingofcopingstrategieseitherindividuallyoringrouphavedemonstratedtheirefficacyinimprovingcaregivers'psychologicalhealth.[18][235] Media Mainarticle:Alzheimer'sdiseaseinthemedia Alzheimer'sdiseasehasbeenportrayedinfilmssuchas:Iris(2001),basedonJohnBayley'smemoirofhiswifeIrisMurdoch;[236]TheNotebook(2004),basedonNicholasSparks'1996novelofthesamename;[237]AMomenttoRemember(2004);Thanmathra(2005);[238]MemoriesofTomorrow(AshitanoKioku)(2006),basedonHiroshiOgiwara'snovelofthesamename;[239]AwayfromHer(2006),basedonAliceMunro'sshortstoryTheBearCameovertheMountain;[240]StillAlice(2014),aboutaColumbiaUniversityprofessorwhohasearlyonsetAlzheimer'sdisease,basedonLisaGenova's2007novelofthesamenameandfeaturingJulianneMooreinthetitlerole.DocumentariesonAlzheimer'sdiseaseincludeMalcolmandBarbara:ALoveStory(1999)andMalcolmandBarbara:Love'sFarewell(2007),bothfeaturingMalcolmPointon.[241][242][243] Alzheimer'sdiseasehasalsobeenportrayedinmusicbyEnglishmusiciantheCaretakerinreleasessuchasPersistentRepetitionofPhrases(2008),AnEmptyBlissBeyondThisWorld(2011),andEverywhereattheEndofTime(2016–2019).[244][245][246]PaintingsdepictingthedisorderincludethelateworksbyAmericanartistWilliamUtermohlen,whodrewself-portraitsfrom1995to2000asanexperimentofshowinghisdiseasethroughart.[247][248] Researchdirections AdditionalresearchonthelifestyleeffectmayprovideinsightintoneuroimagingbiomarkersandbetterunderstandingofthemechanismscausingbothAlzheimer'sdiseaseandearly-onsetAD.[249] Treatmentandprevention Thereisongoingresearchexaminingtheroleofspecificmedicationsinreducingtheprevalence(primaryprevention)and/orprogression(secondaryprevention)ofAlzheimer'sdisease.[250]TheresearchtrialsinvestigatingmedicationsgenerallyimpactAβplaques,inflammation,APOE,neurotransmitterreceptors,neurogenesis,epigeneticregulators,growthfactorsandhormones.[250][251][252]Thesestudieshaveledtoabetterunderstandingofthedisease,butnonehaveledtoaclearordefinitivepreventionstrategy.[250][251] AlthoughitreceivedFDAapproval,aducanumabfailedtoshoweffectivenessinpeoplewhoalreadyhadAlzheimer'ssymptoms.[253] Researchontheeffectsofmeditationonpreservingmemoryandcognitivefunctionsisatanearlystage.[254]A2015reviewsuggeststhatmindfulness-basedinterventionsmaypreventordelaytheonsetofmildcognitiveimpairmentandAlzheimer'sdisease.[255] Theketogenicdietisaveryhigh-fat,adequate-protein,low-carbohydratedietthatisusedtotreatrefractoryepilepsyinchildren.Designedtomimicsomeoftheeffectsoffasting,followingaketogenicdietleadstoelevatedbloodlevelsofmoleculescalledketonebodies:ametabolicstateknownasketosis.Theseketonebodieshaveaneuroprotectiveeffectonagingbraincells,thoughitisnotfullyunderstoodwhy.Limitedresearchintheformofpreclinicaltrials(miceandrats),andsmall-scaleclinical(human)trials,haveexploreditspotentialasatherapyforneurodegenerativedisorderslikeAlzheimer'sdisease.[256] Causeanddiagnosis TheherpessimplexvirusHSV-1hasbeensuggestedasacauseofAD.[10]FungalinfectionofAlzheimer'sdiseasebrainhasbeenproposed.[257] Anumberofbiochemicaltestshavebeendevelopedtoaidearlierdetection.Sometestsinvolvetheanalysisofcerebrospinalfluidforbeta-amyloid,totaltauproteinandphosphorylatedtau181Pproteinconcentrations.[258] 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Furtherreading LibraryresourcesaboutAlzheimer'sDisease Resourcesinyourlibrary Resourcesinotherlibraries HarilalS,JoseJ,ParambiDG,KumarR,MathewGE,UddinMS,et al.(September2019)."AdvancementsinnanotherapeuticsforAlzheimer'sdisease:currentperspectives".TheJournalofPharmacyandPharmacology.71(9):1370–1383.doi:10.1111/jphp.13132.PMID 31304982.S2CID 196616758. Externallinks WikimediaCommonshasmediarelatedtoAlzheimer'sdisease. ClassificationDICD-10:G30,F00ICD-9-CM:331.0,290.1OMIM:104300MeSH:D000544DiseasesDB:490ExternalresourcesMedlinePlus:000760eMedicine:neuro/13PatientUK:Alzheimer'sdiseaseGeneReviews:NBK1161Scholia:Q11081 Alzheimer'sdiseaseatCurlie vteMentaldisorders (Classification)AdultpersonalityandbehaviorSexual Ego-dystonicsexualorientation Paraphilia Fetishism Voyeurism Sexualmaturationdisorder Sexualrelationshipdisorder Other Factitiousdisorder Munchausensyndrome Genderdysphoria Intermittentexplosivedisorder Dermatillomania Kleptomania Pyromania Trichotillomania Personalitydisorder ChildhoodandlearningEmotionalandbehavioral ADHD Conductdisorder ODD Emotionalandbehavioraldisorders Separationanxietydisorder Movementdisorders Stereotypic Socialfunctioning DAD RAD Selectivemutism Speech Cluttering Stuttering Ticdisorder Tourettesyndrome Intellectualdisability X-linkedintellectualdisability Lujan–Frynssyndrome Psychologicaldevelopment(developmentaldisabilities) Pervasive Specific Mood(affective) Bipolar BipolarI BipolarII BipolarNOS Cyclothymia Depression Atypicaldepression Dysthymia Majordepressivedisorder Melancholicdepression Seasonalaffectivedisorder Mania NeurologicalandsymptomaticAutismspectrum Autism Aspergersyndrome High-functioningautism PDD-NOS Savantsyndrome Dementia AIDSdementiacomplex Alzheimer'sdisease Creutzfeldt–Jakobdisease Frontotemporaldementia Huntington'sdisease Mildcognitiveimpairment Parkinson'sdisease Pick'sdisease Sundowning Vasculardementia Wandering Other Delirium Organicbrainsyndrome Post-concussionsyndrome Neurotic,stress-relatedandsomatoformAdjustment Adjustmentdisorderwithdepressedmood AnxietyPhobia Agoraphobia Socialanxiety Socialphobia Anthropophobia Specificsocialphobia Specificphobia Claustrophobia Other Generalizedanxietydisorder OCD Panicattack Panicdisorder Stress Acutestressdisorder PTSD Dissociative Depersonalization-derealizationdisorder Dissociativeidentitydisorder Fuguestate Psychogenicamnesia Somaticsymptom Bodydysmorphicdisorder Conversiondisorder Gansersyndrome Globuspharyngis Psychogenicnon-epilepticseizures Falsepregnancy Hypochondriasis Masspsychogenicillness Nosophobia Psychogenicpain Somatizationdisorder PhysiologicalandphysicalbehaviorEating Anorexianervosa Bulimianervosa Ruminationsyndrome Otherspecifiedfeedingoreatingdisorder Nonorganicsleep Hypersomnia Insomnia Parasomnia Nightterror Nightmare REMsleepbehaviordisorder Postnatal Postpartumdepression Postpartumpsychosis SexualdysfunctionArousal Erectiledysfunction Femalesexualarousaldisorder Desire Hypersexuality Hypoactivesexualdesiredisorder Orgasm Anorgasmia Delayedejaculation Prematureejaculation Sexualanhedonia Pain Nonorganicdyspareunia Nonorganicvaginismus Psychoactivesubstances,substanceabuseandsubstance-related Drugoverdose Intoxication Physicaldependence Reboundeffect Stimulantpsychosis Substancedependence Withdrawal Schizophrenia,schizotypalanddelusionalDelusional Delusionaldisorder Folieàdeux Psychosisandschizophrenia-like Briefreactivepsychosis Schizoaffectivedisorder Schizophreniformdisorder Schizophrenia Childhoodschizophrenia Disorganized(hebephrenic)schizophrenia Paranoidschizophrenia Pseudoneuroticschizophrenia Simple-typeschizophrenia Other Catatonia Symptomsanduncategorized Impulse-controldisorder Klüver–Bucysyndrome Psychomotoragitation Stereotypy vteDiseasesofthenervoussystem,primarilyCNSInflammationBrain Encephalitis Viralencephalitis Herpesviralencephalitis Limbicencephalitis Encephalitislethargica Cavernoussinusthrombosis Brainabscess Amoebic Brainandspinalcord Encephalomyelitis Acutedisseminated Meningitis Meningoencephalitis Brain/encephalopathyDegenerativeExtrapyramidalandmovementdisorders Basalgangliadisease Parkinsonism PD Postencephalitic NMS PKAN Tauopathy PSP Striatonigraldegeneration Hemiballismus HD OA Dyskinesia Dystonia Statusdystonicus Spasmodictorticollis Meige's Blepharospasm Athetosis Chorea Choreoathetosis Myoclonus Myoclonicepilepsy Akathisia Tremor Essentialtremor Intentiontremor Restlesslegs Stiff-person Dementia Tauopathy Alzheimer's Early-onset Primaryprogressiveaphasia Frontotemporaldementia/Frontotemporallobardegeneration Pick's Lewybodiesdementia Posteriorcorticalatrophy Vasculardementia Mitochondrialdisease Leighsyndrome Demyelinating Autoimmune Inflammatory Multiplesclerosis Formoredetailedcoverage,seeTemplate:DemyelinatingdiseasesofCNS Episodic/paroxysmalSeizuresandepilepsy Focal Generalised Statusepilepticus Formoredetailedcoverage,seeTemplate:Epilepsy Headache Migraine Cluster Tension Formoredetailedcoverage,seeTemplate:Headache Cerebrovascular TIA Stroke Formoredetailedcoverage,seeTemplate:Cerebrovasculardiseases Other Sleepdisorders Formoredetailedcoverage,seeTemplate:Sleep CSF Intracranialhypertension Hydrocephalus Normalpressurehydrocephalus Choroidplexuspapilloma Idiopathicintracranialhypertension Cerebraledema Intracranialhypotension Other Brainherniation Reyesyndrome Hepaticencephalopathy Toxicencephalopathy Hashimoto'sencephalopathy StaticEncephalopathy Both/eitherDegenerativeSA Friedreich'sataxia Ataxia–telangiectasia MND UMNonly: Primarylateralsclerosis Pseudobulbarpalsy Hereditaryspasticparaplegia LMNonly: Distalhereditarymotorneuronopathies Spinalmuscularatrophies SMA SMAX1 SMAX2 DSMA1 CongenitalDSMA Spinalmuscularatrophywithlowerextremitypredominance(SMALED) SMALED1 SMALED2A SMALED2B SMA-PCH SMA-PME Progressivemuscularatrophy Progressivebulbarpalsy Fazio–Londe Infantileprogressivebulbarpalsy both: Amyotrophiclateralsclerosis vteAmyloidosisCommonamyloidformingproteins AA ATTR Aβ2M AL Aβ/APP AIAPP ACal APro AANF ACys ABri Systemicamyloidosis ALamyloidosis AAamyloidosis Aβ2M/Haemodialysis-associated AGel/Finnishtype AA/FamilialMediterraneanfever ATTR/Transthyretin-relatedhereditary Organ-limitedamyloidosisHeartAANF/IsolatedatrialBrain Familialamyloidneuropathy ACys+ABri/Cerebralamyloidangiopathy Aβ/Alzheimer'sdisease Kidney AApoA1+AFib+ALys/Familialrenal Skin Primarycutaneousamyloidosis Amyloidpurpura Endocrine Thyroid ACal/Medullarythyroidcancer Pituitary APro/Prolactinoma Pancreas AIAPP/Insulinoma AIAPP/Diabetesmellitustype2 Authoritycontrol:Nationallibraries Spain France(data) Germany Israel UnitedStates Japan CzechRepublic Sweden Retrievedfrom"https://en.wikipedia.org/w/index.php?title=Alzheimer%27s_disease&oldid=1095752063" Categories:Aging-associateddiseasesAlzheimer'sdiseaseAilmentsofunknowncauseAmyloidosisAphasiasCognitivedisordersDementiaEponymsHerpessimplexvirus–associateddiseasesLearningdisabilitiesUnsolvedproblemsinneuroscienceHiddencategories:CS1French-languagesources(fr)CS1Portuguese-languagesources(pt)WikipediaarticlesinneedofupdatingfromFebruary2022AllWikipediaarticlesinneedofupdatingCS1German-languagesources(de)CS1Japanese-languagesources(ja)ArticleswithshortdescriptionShortdescriptionisdifferentfromWikidataWikipediaindefinitelysemi-protectedpagesWikipediaindefinitelymove-protectedpagesWikipediaarticlesinneedofupdatingfromMarch2021UseBritishEnglishfromMarch2022UsedmydatesfromMarch2022Articlescontainingpotentiallydatedstatementsfrom2018AllarticlescontainingpotentiallydatedstatementsWikipediaarticlesneedingclarificationfromDecember2021Articlescontainingpotentiallydatedstatementsfrom2019CommonscategorylinkisonWikidataArticleswithCurlielinksArticleswithBNEidentifiersArticleswithBNFidentifiersArticleswithGNDidentifiersArticleswithJ9UidentifiersArticleswithLCCNidentifiersArticleswithNDLidentifiersArticleswithNKCidentifiersArticleswithSELIBRidentifiersWikipedianeurologyarticlesreadytotranslateWikipediamedicinearticlesreadytotranslate 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